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Lymphocyte Activation & Immune Tolerance. Pin Ling ( 凌 斌 ), Ph.D. ext 5632; lingpin@mail.ncku.edu.tw References: 1. Abbas, A, K. et.al, Cellular and Molecular Immunology (6th ed., 2007), Chapter 9-11. Question. What is happened to the immune system if RAG1 & RAG2 are mutated?.

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Lymphocyte Activation & Immune Tolerance


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lymphocyte activation immune tolerance
Lymphocyte Activation & Immune Tolerance
  • Pin Ling (凌 斌), Ph.D.

ext 5632; lingpin@mail.ncku.edu.tw

  • References:

1. Abbas, A, K. et.al, Cellular and Molecular Immunology (6th ed., 2007), Chapter 9-11

slide2

Question

What is happened to the immune

system if RAG1 & RAG2 are mutated?

  • Severe Combined Immunodeficiency Disease (SCID)
  • Lacking functional T & B cells
outline
Outline
  • Activation of T Lymphocytes
  • B cell Activation & Ab Production
  • Immune Tolerance
  • Summary & Question
key points in t cell activation
Key points in T cell activation
  • Activation of CD4 & CD8 T cells

2. Role of Costimulators in T cell activation

3. Signaling Transduction by the TCR/CD3 complex

4. T cell signal “Attenuation”: Roles of inhibitory receptors & Protein degradation

key concepts in t cell activation i
Key Concepts in T cell Activation-I

1. Adaptive immune responses are initiated and mediated

by T-cell activation (especially CD4 T cells).

2. Naïve T lymphocytes migrate from Thymus to 2o

Lymphoid organs, whereby encounter Ag presented by

APCs (e.g. DCs) and then become activated.

3. T-cell activation requires Two Signals:

- Primary Signal-TCR/CD3 –Ag/MHC complex

- Second Signal (Costimulatory)- Other T cell surface molecules (e.g. CD28) interact with ligands from APCs.

4. T cell responses decline after Antigen (Crisis) is eliminated.

slide7

Phases of T cell Responses

IL-2 – a T cell autocrine factor

slide8

Cross presentation (priming) of Ag to CD8 T cells

DC has an unique feature:

  • Allow protein traffic from endosomal vesicles to the cytosol
  • Ag-MHC-I presentation
  • Ingest virus-infected or tumor cells => CD8 T cells
slide12

The T-cell Immunological Synapse

The interface between

APC cells and T cells:

=> Prolong interaction

=> Enhance signaling

transduction

=> Determine the fate of Effector cells

key concepts in t cell activation ii
Key Concepts in T cell Activation-II

1. Activated CD4 T helper type -1 (Th1) cells regulate the

cell-mediated immunity (CMI) => Macrophages & CD8 T cells.

Th2 cells help Humoral immunity => B cell activation

2. Differentiation of naïve CD8 T cells requires Signals:

- Ag presentation, Cytokines (eg. IL-12), and Effector CD4 T cells in some cases.

  • The Best characterized costimulatory pathway:

CD28 (T cell)-B7 (APC) interaction.

outline1
Outline
  • Activation of T Lymphocytes
  • B cell Activation & Ab Production
  • Immune Tolerance
  • Summary & Question
key points in b cell activation ab production
Key points in B cell activation & Ab production
  • Overview of B cell activation

2. Signaling Transduction by BCR & its Co-receptor

3. Mechanisms of CD4 T helper cell-mediated B cell activation

4. The Germinal Center Reaction:

- Isotype switching

- Affinity maturation (Somatic Hypermutation)

key concepts in b cell activation i
Key Concepts in B cell Activation-I

1. B cell activation mediates Humoral Immune Responses.

2. Activating B cells => Ab responses => protein Ag

=> Require CD4 T helper cells

=> These protein Ag => T-dependent (TD) Ag

3. Activating B cells => Ab responses to multivalent Ags

w/ repeating epitopes (lipids, polysaccharides)

=> No CD4 T helper cells

=> These lipid & polysaccharide Ags

=> T-independent (TI) Ag

4. Heavy chain isotype switching & Hypermutation are

often seen in T cell-dependent humoral immune responses.

5. Primary & 2nd Ab responses differ qualitatively &

quantitatively.

slide27

Germinal center reactions in T cell-mediated Ab responses

Germinal centers (2nd

follicle)

1. T-dep B cell activation

2. Somatic

hypermutation

3. Isotype switching

4. Memory B cells

slide29

Ig Heavy chain isotype switching-II

1. AID (Activation-

Induced Deaminase)

, ApeI endonuclease

& UNG (Uracil N

Glycosylase) but not

RAG.

2. Other DNA repair proteins

3. Recognize Ig exon or Switch region

slide31

Somatic Hypermutation in Ig V region

AID is required in this process.

slide32

B cell selection in Germinal Centers

Only B cells w/ a

high affinity for

Ag on follicular

DCs (FDCs)

=> Survive

outline2
Outline
  • Activation of T Lymphocytes
  • B cell Activation & Ab Production
  • Immune Tolerance
  • Summary & Question
key concepts in immune tolerance
Key Concepts in Immune Tolerance

1. Self-tolerance may be induced in immature self-reactive

lymphocytes in primary lymphoid organs (Central tolerance)

or mature lymphocytes in peripheral sites (Peripheral

tolerance).

2. Central Tolerance => Cell Death (T & B cells)

(Negative selection) => Receptor Editing (B cells)

=> A change in functional abilities

(Regulatory T cells)

3. Peripheral Tolerance

Mature lymphocytes  self Ags => No response (Anergy)

=> Cell Death

4. Foreign Ags may be administered in ways that inhibit immune

responses by inducing tolerance.

outline3
Outline
  • Activation of T Lymphocytes
  • B cell Activation & Ab Production
  • Immune Tolerance
  • Summary & Question
summary
SUMMARY

1. T-cell activation requires “Two Signals”:

- Primary Signal-TCR/CD3 –Ag/MHC complex

- Second Signal (Costimulatory)- Other T cell surface molecules (eg. CD28) interact with ligands from APCs.

2. B cell activation mediates “Humoral Immune Responses”.

Isotype switching & Hypermutation are key features

in T cell-dep humoral immune responses.

3. Self-tolerance may be induced in immature self-reactive

lymphocytes in primary lymphoid organs (Central

tolerance) or mature lymphocytes in peripheral sites

(Peripheral tolerance).

4. The failure of self tolerance leads to autoimmune

diseases.

slide47

Question

Have you learned something from

this series of Immunology Lectures?

  • Yes
  • More or less
  • Not Sure
  • Definitely Not